Neurol Med Chir (Tokyo) 43, 447¿451, 2003

Central Nervous System Lesions Associated With
Hereditary Hemorrhagic Telangiectasia
—Three Case Reports—
Kazuyuki KUWAYAMA, Kensaku TAKASE, Michiharu KASHIHARA,
Hideki HONDO, Toshio SHIGEKIYO*, Osamu TAKIMOTO**,
and Shunji MATSUBARA**
Departments of Neurosurgery and *Internal Medicine, Tokushima Prefectural Central Hospital,
Tokushima; **Department of Neurological Surgery, School of Medicine,
The University of Tokushima, Tokushima

Abstract
Hereditary hemorrhagic telangiectasia (HHT) is easily overlooked in patients with central nervous
system (CNS) lesions. Our clinical experience of three patients with CNS lesions associated with
HHT stresses the importance of considering HHT. A 23-year-old male presented with consciousness
disturbance and right hemiparesis. Emergency cerebral digital subtraction angiography revealed occlusion of the left middle cerebral artery and the left anterior cerebral artery. Pulmonary arteriography showed three pulmonary arteriovenous malformations (AVMs). A 62-year-old male presented
with consciousness disturbance and sensory aphasia. Magnetic resonance imaging revealed a ringenhanced lesion in the left temporal lobe which was removed by left frontotemporal craniotomy. The
diagnosis was brain abscess. Chest computed tomography (CT) revealed two pulmonary AVMs. A 32year-old female presented with progressive mild weakness in her left hand. Initial CT showed subcortical hemorrhage in the right frontal lobe. Cerebral angiography revealed no vascular malformations, but chest CT disclosed five pulmonary AVMs. All three patients had a family history of HHT. The
possibility of HHT is important to consider in patients with cerebrovascular disease (CVD) or brain
abscess to prevent complications, not only in the patients but also their blood relatives. Therefore, the
medical and family history of patients with CVD or brain abscess should be investigated and HHT
should be considered during the physical examination.
Key words: hereditary hemorrhagic telangiectasia,
pulmonary arteriovenous malformation

cerebrovascular disease,

Introduction

cerebral abscess,

hemorrhage which were associated with HHT.

Case Reports

Hereditary hemorrhagic telangiectasia (HHT), also
known as Rendu-Osler-Weber disease, is a rare
autosomal-dominant disorder characterized by
multiple mucocutaneous telangiectases and associated vascular malformations that can result in
hemorrhagic complications in multiple organ
systems. Patients with HHT frequently present with
central nervous system (CNS) complications as
neurological emergencies. However, the possibility
of HHT is easily overlooked. We describe cases of
cerebral embolus, cerebral abscess, and subcortical

Case 1: A 23-year-old man suffered right hemiparesis followed by sudden loss of consciousness and
was transferred to the emergency department of our
hospital. On arrival, he was lethargic and exhibited
motor aphasia and right hemiplegia. Blood analysis
showed indications of polycythemia (red blood cells
579 × 104/mm3, hemoglobin 17.6 g/dl). He had a
history of epistaxis since childhood and had
experienced migraine episodes since the age of 14

Received January 8, 2003;
Accepted April 3, 2003
Author's present address: K. Kuwayama, M.D., Department of Neurosurgery, Kochi Red Cross Hospital, Kochi, Japan.

447

448

Fig. 1

K. Kuwayama et al.

Case 1. Emergency left carotid angiograms, (A) anteroposterior view revealing
occlusion of the middle cerebral artery
(arrow), and (B) lateral view revealing occlusion of the middle cerebral artery (arrow)
and anterior cerebral artery (arrowhead).

years. His father also suffered from recurrent
epistaxis.
Computed tomography (CT) on admission revealed no abnormality. Emergency cerebral digital
subtraction angiography (DSA) was performed. Left
carotid angiography revealed occlusion of the distal
horizontal segment of the middle cerebral artery (M1
distal) and the A4 segment of the callosomarginal
artery (Fig. 1). Selective intra-arterial fibrinolysis
with urokinase (54 × 104 IU) was performed. The
left M1 and A4 were recanalized after 90 minutes, but
not the anterior branch of the M2 segment.
Magnetic resonance (MR) imaging showed a
hyperintense area in the frontal and temporal lobes
around the left sylvian fissure 4 days after the onset
(Fig. 2). Transthoracic echocardiography disclosed
no thrombus in the heart. Systolic function in the
left ventricle was normal and no valvular disease
was present. Blood coagulation analysis disclosed
no abnormal findings. Chest radiography revealed
an abnormal shadow in the left lung, leading us to
suspect HHT. This suspicion was clinically confirmed by the detection of telangiectases on the
tongue and nasal mucous membrane. Chest CT and
pulmonary DSA revealed three arteriovenous
malformations (AVMs): 1.8 cm in diameter at A8,
and 1.4 cm and 2 cm in diameter at A9 in the left
lung (Fig. 3). He was treated by transarterial embolization using detachable coils. His right hemiparesis
gradually improved (upper limb manual muscle test
grade 1, lower limb manual muscle test grade 3) and
he was discharged 4 months after the onset.
Case 2: A 62-year-old man lost consciousness for a
few minutes after drinking alcohol and was trans-

Fig. 2

Case 1. Axial T2-weighted magnetic
resonance image obtained 4 days after onset
showing a hyperintense area around the left
sylvian fissure.

Fig. 3

Case 1. Left pulmonary angiogram revealing three arteriovenous malformations.

ferred to our hospital. On arrival, he was relatively
alert and as he had been drinking alcohol just prior
to his transfer, he was advised to consult a local
clinic. He returned to his home where his level of
consciousness gradually deteriorated. On the following day he reported to a local clinic where MR imag-

Neurol Med Chir (Tokyo) 43, September, 2003

CNS Lesions Associated With HHT

Fig. 5
Fig. 4

Case 2. Preoperative axial T1-weighted
magnetic resonance image with gadolinium
revealing a ring-enhanced lesion in the left
temporal lobe.

ing showed a mass lesion. He was then referred to
our hospital. He had suffered from epistaxis since
childhood, and had had bone myelitis in the right
tibia in December 1999. His mother had HHT and
his sister had telangiectasia. He also had a 10-day
history of left temporalgia.
On admission he was lethargic and confused, and
manifested sensory aphasia. Blood analysis indicated mild infection (white blood cells 9500/mm3, red
blood cells 547 × 104/mm3, hemoglobin 15.6 g/dl,
hematocrit 44.7%, platelet 17.1 × 104/mm3, C-reactive protein 1.7 mg/dl). MR imaging performed at the
other hospital also showed a ring-enhanced lesion in
the left temporal lobe and perifocal edema (Fig. 4).
Chest radiography showed right perihilar consolidation and further examination of the lung was
planned after treating the intracranial lesion. He
was treated with prednisolone and drip infusion of
glycerol starting on the day of admission. His
consciousness disturbance was improved on the day
after admission and his sensory disturbance improved gradually. The differential diagnosis included glioblastoma, metastatic brain tumor, and brain
abscess.
He underwent left frontotemporal craniotomy 10
days after admission. The mass contained white pus
and was surrounded by a cyst wall. The medial wall
of the cyst was not removed to avoid iatrogenic
neurological deficits. Culture of the purulent mass
content revealed Peptostreptococcus and Fusobacterium. Postoperatively, he had meningitis but re-

Neurol Med Chir (Tokyo) 43, September, 2003

449

Case 3. Computed tomography scan obtained at initial admission revealing subcortical hemorrhage in the right frontal lobe.

covered after administration (40 days) of antibiotics.
MR imaging obtained 22 days after the onset
showed an enhanced lesion around the space caused
by cyst removal. He again experienced nosebleeds
and we suspected HHT. Further examination
showed telangiectases of the nasal, tongue,
esophageal, and stomach membranes. Chest CT and
three-dimensional CT angiography disclosed two
AVMs: 1 cm in diameter at A2 and 1.5 cm in diameter at A3. The diagnosis was HHT. He was
discharged ambulatory and was hospitalized again 2
months later for the treatment of the pulmonary
AVMs by transarterial embolization using detachable coils.
Case 3: A 32-year-old woman suffered sudden onset
of gradually worsening monoparesis of her left arm.
One day after the onset, she reported to the emergency department of our hospital. Neurological examination revealed monoplegia of her left arm. The
results of blood analysis were within normal limits.
She had suffered from epistaxis since childhood,
and had undergone resection of the inferior lobe of
the left lung for pulmonary AVMs at age 15 years.
Her paternal relatives had a history of recurrent
epistaxis.
CT revealed subcortical hemorrhage, 2 cm in diameter, in the right frontal lobe (Fig. 5). MR imaging
found no abnormalities other than the subcortical
hemorrhage 4 days after onset. Cerebral DSA disclosed no cerebrovascular malformations 6 days
after onset. We suspected HHT on the basis of her
past history and family history. The clinical diagno-

K. Kuwayama et al.

450

sis of HHT was based on the further finding of
telangiectases on the tongue and nasal mucous
membrane. Chest CT, three-dimensional CT angiography, and pulmonary DSA revealed five AVMs:
3 mm (n ＝ 2) and 7 mm (n ＝ 1) in diameter in the
left lung, and 5 mm (n ＝ 2) in diameter in the right
lung. All pulmonary AVMs were supplied by lowflow, small feeding arteries. She was referred to the
department of surgery in our hospital for follow up.
The monoparesis of her left arm gradually improved
(manual muscle test grade 4) and she was discharged
40 days after the onset.

Discussion
HHT is a rare autosomal-dominant hereditary disorder with an estimated prevalence of 1 in 10,000.4)
There is no family history of HHT in 15–30% of
cases.9) The clinical diagnosis of HHT is based on
four criteria: Occurrence of spontaneous, recurrent
epistaxis; presence of telangiectasia at multiple
characteristic sites, including the lips, oral cavity,
fingers, nose, and gastrointestinal tract; findings of
visceral AVM in the lung, brain, liver, and spine;
and a family history of HHT. The definitive diagnosis of HHT requires at least three of these criteria.10)
Epistaxis is the most common manifestation of HHT
and is usually the earliest symptom, appearing at a
mean age of 12 years. As many as 95% of affected individuals eventually experience recurrent epistaxis.
The age at onset is 10 years in approximately one
third of patients, and by age 21 years in the remaining patients.1) Gastrointestinal bleeding occurs in
one third of patients with HHT, but the age at onset
tends to exceed 50 years.5)
The two main genetic forms of HHT are designated HHT1 and HHT2. HHT1 is caused by a mutation
in the endoglin gene located on chromosome 9q33q34. HHT2 is caused by a mutation in the activin
receptor-like kinase-1 gene located on chromosome
12q1. HHT1 may be associated with a high incidence of AVMs.11) Arterialized veins contained endoglin-positive fibroblasts in both the adventitia and
the perivascular connective tissue of patients with
cerebral AVMs, suggesting that endoglin is active
in vascular remodeling.7) As all of our patients
manifested at least three of the criteria for the
clinical diagnosis of HHT, we did not perform gene
analysis. We suggest that confirmatory gene analysis
is advisable if fewer than three criteria are present
or in individuals with a family history of HHT.
HHT is also associated with cerebrovascular
malformations. Cerebrovascular malformations
occur in 12–36% of patients with HHT, of which
4.9–11% are cerebral AVMs.3,9,13) Intravenous DSA

found cerebral AVMs in 11% of 196 patients with
HHT.13) The estimated bleeding risk of one AVM per
year was 0.36–0.56%. Investigation of the angiographic characteristics of AVMs associated with
HHT found that multiple cortical micro-AVMs are
highly suggestive of HHT.8) Cerebral DSA in our
Case 3 revealed no abnormality, but cryptic AVMs
may have manifested as telangiectasia. Alternatively, micro-AVMs could not be detected because of
compression by the hematoma. We are planning to
repeat cerebral DSA in this patient.
Pulmonary AVMs are frequently encountered in
patients with HHT, often accompanied by dyspnea
or hemoptysis. Screening for pulmonary AVMs is
usually performed by arterial blood gas analysis,
chest radiography, and physical examination.2) The
shunting of air, thrombi, and bacteria passing
through pulmonary AVMs, bypassing the filtering
capabilities of the lungs, may result in transient
ischemic attacks, embolic stroke, or cerebral abscess.4,6,12) Approximately 20% of patients with HHT
will develop pulmonary AVM, and 25–33% of such
patients will develop cerebral ischemic symptoms.
Brain abscesses will occur in 5–9% of these patients.6,12) Study of 321 patients with HHT at a single institution found pulmonary AVM in 22.1%, of
whom 29.6% had a history of cerebral infarction or
transient ischemic attacks, and 7% had a history of
at least one cerebral abscess. AVMs with feeding
vessels that exceed 3 mm in diameter require occlusion with detachable coils or surgery.6) The pulmonary AVMs in our Cases 1 and 2 could have resulted in cerebral embolism and brain abscess. Earlier
treatment of these pulmonary AVMs could have
prevented the CNS manifestations. All pulmonary
AVMs were small and of low flow in Case 3. This
patient is being followed up by the department of
surgery in our hospital.
Our Case 1 presented at the emergency room and
no inquiry into his past history of epistaxis was
made at the time of presentation. The abnormal
shadow on chest radiography was missed by
neurosurgeons not trained in the detection of fine
lesions. This case illustrates the importance of
obtaining detailed patient and family medical
histories. In the absence of the suspicion of HHT,
the characteristic findings were easy to miss in this
patient. In Case 2, the history of epistaxis was
missed. Telangiectasia of the skin and tongue was
detected but we did not immediately connect these
findings with HHT. Case 3 had a history of resection
of the inferior lobe of the left lung and we considered HHT because of our previous experiences
with Cases 1 and 2. Therefore, the diagnosis of HHT
was established early and this patient was treated

Neurol Med Chir (Tokyo) 43, September, 2003

CNS Lesions Associated With HHT
appropriately. Cerebrovascular disease (CVD) is
almost always of sudden onset and most patients
with CVD are first seen in the emergency room
where there is insufficient time to acquire a detailed
medical and family history. However, telangiectasia
of the tongue and fingers is easily detected and chest
radiography and blood gas analysis for hypoxia
should be performed routinely even in emergency
cases. Therefore, the diagnosis of HHT can be established in patients with a history of CVD or brain abscess. The medical history and physical findings
should be re-evaluated in patients undergoing longterm follow up. The association of HHT is important
to identify in patients with CVD or brain abscess
because early diagnosis facilitates the treatment of
lesions. The treatment of pulmonary AVMs is
especially important to avoid progression to
cerebral embolism or cerebral abscess. Furthermore, because HHT is a hereditary disease, the
family of patients treated under the diagnosis of
HHT should be screened for AVMs and other
lesions.
Our experience with these patients with CNS
lesions found to be associated with HHT suggests a
detailed medical and family history should be obtained early in patients with CVD or brain abscess
and the possibility of HHT should be considered at
physical examination.

References
Assar OS, Friedman CM, White RI: The natural history of epistaxis in hereditary hemorrhagic telangiectasia. Laryngoscope 101: 977–980, 1991
2) Cormac O, Maher MD, David G, Piepgras MD,
Brown RD Jr, Jonathan A, Friedman MD, Pollock BE:
Cerebrovascular manifestations in 321 cases of
hereditary hemorrhagic telangiectasia. Stroke 32:
877–882, 2001
3) Fulbright RK, Chaloupka JC, Putman CM, Sze GK,
Merrian MM, Lee GK, Fayad PB, Awad IA, White RI:
MR of hereditary hemorrhagic telangiectasia: prevalence and spectrum of cerebrovascular malformations. AJNR Am J Neuroradiol 19: 477–484, 1998
4) Guttmacher AE, Marchuk DA, White RIJ: Hereditary
hemorrhagic telangiectasia. N Engl J Med 333:
918–924, 1995

5)

6)

7)

8)

9)

10)

11)

12)

1)

Neurol Med Chir (Tokyo) 43, September, 2003

13)

451

Kjeldsen AD, Kjeldsen J: Gastrointestinal bleeding in
patients with hereditary hemorrhagic telangiectasia.
Am J Gastroenterol 95: 415–418, 2000
Lee DW, White RI, Egglin TK, Pollak JS, Fayad PB,
Wirth JA, Rosenblatt MM, Dickey KW, Burdge CM:
Embolotherapy of large pulmonary arteriovenous
malformations: long-term results. Ann Thorac Surg
64: 930–939, 1997
Matsubara S, Bourdeau A, ter Brugge KG, Wallace C,
Letarte M: Analysis of endoglin expression in normal
brain tissue and cerebral arteriovenous malformations. Stroke 31: 2653–2660, 2000
Matsubara S, Manzia JL, ter Brugge KG, Willinsky
RA, Montanera W, Faughnan ME: Angiographic and
clinical characteristics of patients with cerebral
arteriovenous malformations associated with hereditary hemorrhagic telangiectasia. AJNR Am J Neuroradiol 21: 1016–1020, 2000
Roman G, Fisher M, Perl DP, Poser CM: Neurological manifestations of hereditary hemorrhagic telangiectasia: Report of 2 cases and a review of the literature. Ann Neurol 4: 130–144, 1978
Shovlin CL, Guttmacher AE, Buscarini E, Faughnan
ME, Hyland RH, Westermann CJ, Kjeldsen AD,
Plauchu H: Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).
Am J Med Genet 91: 66–67, 2000
Shovlin CL, Hughes JMB, Scott J, Seidman CE,
Seidman JG: Characterization of endoglin and
identification of novel mutations in hereditary
hemorrhagic telangiectasia. Am J Hum Genet 61:
68–79, 1997
White RI, Lynch-Nyhan A, Terry P, Buescher PC,
Farmlett EJ, Charnas L, Shuman K, Kim W, Kinnison
M, Mitchell SE: Pulmonary arteriovenous malformations: techniques and long-term outcome of embolotherapy. Radiology 169: 663–669, 1988
Willemse RB, Mager JJ, Westermann CJJ, Overtoom
TTC, Mauser H, Wolbers JG: Bleeding risk of
cerebrovascular malformations in hereditary hemorrhagic telangiectasia. J Neurosurg 92: 779–784, 2000

Address reprint requests to: K. Kuwayama, M.D., Department of Neurosurgery, Kochi Red Cross Hospital,
2–13–51 Shinhon–machi, Kochi 780–8562, Japan.
e-mail: kny1717＠yahoo.co.jp